The World Health Organization identifies methamphetamine as the second most widely abused illicit drug after marijuana, and abuse of prescription amphetamines in the US is increasing. Drug addiction is a chronic and relapsing disorder, and relapse is thought to arise, in part, from the need to alleviate negative withdrawal symptoms such as anxiety and depression. Amphetamine abuse is associated with a withdrawal syndrome that includes increased anxiety states during drug abstinence. We have developed a rat model of heightened anxiety during amphetamine withdrawal and have identified changes in serotonergic neurotransmission within several key limbic brain areas that are important for fear, anxiety and stress states. The goal of the current proposal is to elucidate the mechanisms by which amphetamine withdrawal results in altered serotonergic neurotransmission, and directly relate these to heightened anxiety states and stress sensitivity during withdrawal. Furthermore this proposal will test traditional and novel pharmacotherapies in this rat model of amphetamine withdrawal, to determine whether normalizing serotonergic function in the brain reverses heightened anxiety states that are observed during abstinence from amphetamine. PUBLIC HEALTH RELEVANCE: Transition from amphetamine use to addiction may result, in part, from the need to alleviate dysphoric states, including heightened anxiety that emerge during drug abstinence. It is essential to understand the neurobiology underlying anxiety states during amphetamine withdrawal to identify potential pharmacotherapeutics, although very little research has been focused on this aspect of drug abuse. The current proposal will elucidate the neural mechanisms by which amphetamine withdrawal results heightened anxiety states and will test traditional and novel pharmacotherapies in a rat model of amphetamine withdrawal.